This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Hypothesis: Existing treatments for major depressive disorder (MDD) generally take weeks to months to exert their maximal benefit. Given the morbidity and mortality resulting from failure to treat depressive symptoms in a timely fashion, there is an urgent need to develop rapidly-acting treatments, as well as to identify optimal continuation treatment approaches. Ketamine, a high-affinity N-methyl-D-aspartate (NMDA) glutamate receptor antagonist, has been used as a standard intravenous (IV) anesthetic agent for many years in both pediatric and adult patients, with IV doses of 2 mg kg-1 producing surgical anesthesia within 30 seconds and lasting 5-10 minutes. Beyond its well-established role in anesthesia and pain management, there is emerging evidence that ketamine may have rapid antidepressant properties for patients with severe mood disorders. Two published studies have now shown that a single 0.5 mg kg-1 dose of ketamine in patients with treatment-resistant MDD causes a robust antidepressant effect within 2 hours, and many patients subsequently maintain a mood improvement for several days (though all had undergone relapse within 2 weeks). However, ketamine s effectiveness in treating depression is still considered a preliminary finding, especially given that the two studies described previously used an inactive placebo (IV saline) in a within-group RCT, in which it was difficult to maintain the blind. Crossing participants over from one treatment to another was problematic in those who had received ketamine on the first infusion day. In the present study we instead propose the use of an active control (IV midazolam) in a between-groups RCT. This will provide much-needed additional evidence that ketamine is indeed effective in treating depression. This research protocol will, in patients with TRD under double-blind conditions, test the antidepressant efficacy of IV ketamine administration in comparison with that of IV midazolam administration. Thus, the study aims: SPECIFIC AIM 1: To test whether a single infusion of IV ketamine exerts superior antidepressant effects compared to an active control agent (IV midazolam) in patients with TRD. Hypothesis 1a: TRD patients randomized to IV ketamine show greater improvement in depressive symptoms compared to patients randomized to IV midazolam, as determined by the change in the MADRS score 24 hours following infusion. Hypothesis 1b: TRD patients randomized to IV ketamine have a higher response rate compared to patients randomized to IV midazolam at 24 hours. SPECIFIC AIM 2: To characterize the durability of antidepressant benefit and test whether treatment with IV ketamine is associated with superior antidepressant effects over the subsequent 7-day interval. Hypothesis 2: TRD patients randomized to ketamine will demonstrate greater durability of antidepressant response than patients randomized to midazolam. SPECIFIC AIM 3: To examine the safety and tolerability of the interventions. Hypothesis 3: Moderate or severe side effects or adverse events will be infrequent or absent. The study interventions will not be associated with distinctly different rates of side effects or adverse events requiring discontinuation from the study.